IL-9 is required for multi-cytokine producing tissue-resident memory CD4+ T cell-dependent allergic airway recall responses
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ABSTRACT:
PROVIDER: PRJNA788490 | ENA |
REPOSITORIES: ENA
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Project description:Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses are not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we have characterized a sub-population of Th2 cells that secretes IL-9 as an obligate effector cytokine. IL-9-secreting cells have a resident memory T cell phenotype and blocking IL-9 during a recall challenge significantly diminishes airway inflammation and airway hyperreactivity. T cells secrete IL-9 in response to allergen recall and secretion is amplified by IL-33. Using scRNA-seq and scATAC-seq, we define the cellular identity of a distinct populations of T cells with pro-allergic cytokine patterns. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multi-cytokine producing cell population is required for an allergen recall response.
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Project description:Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. Herein, we report the identification of a novel regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate liver kinase B1 (LKB1) mediated activation of salt-inducible kinases (SIKs) epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed SIK mediated phosphorylation dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels which correlated with both global and cytokine loci specific reductions in the activating transcription mark, histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine upon re-stimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a novel target for enhancing effector T cell functionality.
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Project description:Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. Therefore, there should be mechanisms to maintain the capacity of ILC2s to produce TH2 cytokines under chronic inflammatory conditions. Here, we report that Runx proteins are essential to prevent exaggerated activation of ILC2, in part by antagonizing GATA-3 function at steady state. However, during allergic inflammation, the absence of Runx in ILC2s impaired their ability to proliferate and produce effector TH2 cytokines and chemokines, but instead induced expression of T cell exhaustion markers including IL-10 and TIGIT. These exhausted ILC2s were unabale to induce type 2 immune responses against repeated allergen inhalation. Thus, Runx proteins protect ILC2s from exhaustion during continuous allergic inflammation.
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Project description:We report RNA-seq data from distinct memory CD4+ T cell subsets in a murine model of allergic asthma.
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Project description:Obesity is associated with severe, difficult to control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment strategy. Using a mouse model of house dust mite (HDM) induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ); we investigated the effects of obesity and mROS on airway inflammation, remodelling and airway hyperreactivity (AHR). HDM induces airway inflammation, remodelling and hyperreactivity in both lean and obese mice. Obese allergic mice showed increased lung tissue eotaxin levels, airway tissue eosinophilia and AHR when compared to lean allergic mice. MitoQ reduced markers of airway inflammation, remodelling and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obeseHDM mice. mROS regulates cell signalling by protein oxidation of multiple downstream targets: MitoQ reduced HDM-induced cysteine-sulfenylation of several proteins including those involved in the unfolded protein response (UPR). In summary, mROS mediates the development of allergic airway disease and hence MitoQ might be effective for the treatment for asthma, and specific features of obese asthma.
2023-06-02 | PXD029715 | Pride
Project description:Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T-cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses using two different viral systems. Interestingly, TSLP limited the primary CD8+ T cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells generated after influenza infection. However, TSLP inhibited memory CD8+ T cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8+ T cell responses in response to viral infection, findings with potential translational implications.
2021-01-05 | GSE156875 | GEO
Project description:RATIONALE: The development and progression of asthma are strongly influenced by environmental exposures. We have demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. OBJECTIVES: Since there is conflicting evidence on the role of folate in modifying allergic airway disease risk, we hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (MTHFR) activity would reduce the allergic airway disease phenotype. METHODS: Using a house dust mite (HDM) induced model of allergic airway disease, we tested the effect of MTHFR on disease severity. MEASUREMENTS AND MAIN RESULTS: Loss of MTHFR alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6MTHFR-/- mice demonstrate significantly less airway hyerreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6MTHFR-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and IL-4/IL-5 cytokine concentrations. The effect of MTHFR loss on HDM-induced allergic airway disease was reversed by betaine supplementation. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6MTHFR-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations. CONCLUSION: Collectively, these findings indicate that single carbon metabolism warrants further investigation as a disease modifier in allergic airway disease.
2018-01-31 | GSE71822 | GEO